&#34;Triazolo-pyrimidine intermediates&#34;

ABSTRACT

There are disclosed a β-lactam compound represented by the formula (I): ##STR1## wherein R 1  represents an acyl group; M represents a hydrogen atom, a protective group of an eliminatable group which is easily hydrolyzable in a human body; B represents a group represented by the formula (b): ##STR2## where at least one of R 2 , R 3  and R 9  represent a group represented by the formula: -A-OR 4  where R 4  represents a hydrogen or a lower alkyl group; and A represents a straight or branched alkylene group having 1 to 6 carbon atoms; and a remaining group or groups are each independently a hydrogen atom; a cyano group; a lower alkyl group which may be substituted by a halogen atom; a carbamoyl group which may be substituted by a lower alkyl group; a cycloalkyl group; or a carboxyl group which may be substituted by a protective group of an eliminatable group which is easily hydrolyzable in a human body, and also when R 9  is -A-OR 4 , R 2  and R 3  may be combined with each other to form an alkylene group having 3 to 4 carbon atoms; and Z represents a nitrogen atom or a group represented by the formula: C-R 10  where R 10  represents a hydrogen atom, a carboxyl group or a lower alkyl group which may be substituted by a hydroxy group or a lower alkoxy group, 
     or its pharmaceutically acceptable salt, and a process for preparing the same, an intermediate for synthesis of the same and a medicinal composition for bacterially infectious disease therapy containing the same.

This is a division of application Ser. No. 222,404, filed July 21, 1988.

BACKGROUND OF THE INVENTION

This invention relates to novel β-lactam compounds, more particularly toa novel cephalosporin series compound useful for antibiotics, a methodfor preparing the same, a synthetic intermediate and use thereof.

Heretofore, it has been known that β-lactam series antibiotics haveantibacterial activities to gram positive bacteria and gram negativebacteria and many of these compounds have actually been appliedtherefor. Among them, compounds which are called to as the thirdgeneration cephalosporin series antibiotics have wide range ofantibacterial spectrum and particularly are evaluated in the clinicalfield.

However, while the several kinds of the above compounds have been usedin practical use, all of them are inferior in their antibacterialactivities to Pseudomonos aeruginosa. Further, some kinds of them arefinely effective to gram negative bacteria other than Pseudomonosaeruginosa but there are disadvantages that they have lower activitiesto gram positive bacteria and also, accompanied with the increasedfrequency in use of cephalosporins, strains which aquired crossresistance to β-lactams are gradually increasing.

SUMMARY OF THE INVENTION

The present inventors have intensively studied, by referring to theabove situation, concerning a compound which has potent antibacterialactivities in extremely wide ranges, and as a result, have found thatthe compound represented by the formula (I) has excellentcharacteristics as a medicinal composition for bacterially infectiousdisease (microbism) therapy and accomplished the present invention.

That is, the present invention relates to a β-lactam compoundrepresented by the formula (I): ##STR3## wherein R₁ represents an acylgroup; M represents a hydrogen atom, a protective group or aneliminatable group which is easily hydrolyzable in a human body; Brepresents a group represented by the formula (b): ##STR4## where atleast one of R₂, R₃ and R₉ represent a group represented by the formula:-A-OR₄ where R₄ represents a hydrogen or a lower alkyl group; and Arepresents a straight or branched alkylene group having 1 to 6 carbonatoms; and a remaining group or groups are each independently a hydrogenatom; a cyano group; a lower alkyl group which may be substituted by ahalogen atom; a carbamoyl group which may be substituted by a loweralkyl group; a cycloalkyl group; or a carboxyl group which may besubstituted by a protective group or an eliminatable group which iseasily hydrolyzable in a human body, and also when R₉ is -A-OR₄, R₂ andR₃ may be combined with each other to form an alkylene group having 3 to4 carbon atoms; and Z represents a nitrogen atom or a group representedby the formula: C-R₁₀ where R₁₀ represents a hydrogen atom, a carboxylgroup or a lower alkyl group which may be substituted by a hydroxy groupor a lower alkoxy group,

or its pharmaceutically acceptable salt, a method for preparing thesame, an intermediate for synthesis thereof and a medicinal compositionfor bacterially infectious disease therapy containing said compound asthe active ingredient.

Further, hydrates or organic solvates of the compound represented by theabove formula (I) are included in the scope of the present invention asa matter of course.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Next, each groups which are summarily shown in the above formula (I) areexplained in more detail.

Explanation of R₁

An acyl group represented by R₁ can be derived from a carboxylic acid,and includes all organic groups used in cephalosporanic chemistry.

Particularly preferred acyl group may include a 2-(2-thienyl)acetylgroup and a group represented by the formula (C): ##STR5## wherein R₇represents a heterocyclyl group; and R₈ represents a hydrogen atom, alower alkyl group or a group represented by the formula (d), (e) or (f):##STR6## where R₅ and R₆ each independently represent a hydrogen atom ora lower alkyl group; R" represents a hydrogen atom or a protectivegroup; and X represents a hydrogen atom, a lower alkyl group, a loweralkoxy group or a halogen atom, or a group represented by the formula(g): ##STR7## wherein R' represents a hydrogen atom or a protectivegroup, and an acyl group as disclosed in Japanese Provisional PatentPublications Nos. 16487/1987, 33185/1987, 108997/1977, 49382/1983,74680/1983, 139381/1984, 167576/1984, 163884/1985 267583/1986.

In the above, an acyl group represented by the formula (a) is preferredfor injection. ##STR8## wherein R₅, R₆, R', R" and X have the samemeanings as defined above.

In the above, as a lower alkyl group represented by R₅, R₆ and R₈, theremay be mentioned a straight or branched alkyl group having 1 to 3 carbonatoms. For example, there may be mentioned a methyl group, an ethylgroup, an n- or iso-propyl group, etc. As the protective grouprepresented by the R', there may be mentioned a diphenylmethyl group, at-butyl group, a p-nitrobenzyl group, a trimethylsilyl group, etc. Asthe protective group represented by the R", there may be mentioned alower acyl group such as an acetyl group, a propionyl group, etc. and alower alkoxycarbonyl group such as a methoxycarbonyl group, anethoxycarbonyl group, etc. As the halogen atom represented by X, theremay be mentioned a chlorine atom, a bromine atom, a fluorine atom, etc.,and as the lower alkyl group, there may be mentioned a straight orbranched alkyl group having 1 to 3 carbon atoms, for example, a methylgroup, an ethyl group, an n- or iso-propyl group, etc., and as the loweralkoxy group, there may be mentioned an alkoxy group having 1 to 3carbon atoms, for example, a methoxy group, an ethoxy group, an n- orisopropoxy group, etc.

Explanation of M

M is a hydrogen atom, a protective group or an eliminatable group whichis easily hydrolyzable in a human body.

When the M is a protective group, there may be mentioned adiphenylmethyl group, a t-butyl group, a p-nitrobenzyl group, atrimethylsilyl group, etc.

Further, when the M is an eliminatable group which is easilyhydrolyzable in a human body, there may be mentioned an acetoxymethylgroup, an α-acetoxyethyl group, a pivaroyloxymethyl group, anα-ethoxycarbonyloxymethyl group, an α-methoxycarbonyloxymethyl group, anα-methoxycarbonyloxyethyl group, an α-ethoxycarbonyloxyethyl group, a1-indanyl group, a phthalidyl group, a5-methyl-2-oxo-1,3-dioxol-4-yl-methyl group and the like.

Explanation of R₂, R₃ and R₉

At least one of R₂, R₃ and R₉ is/are a group represented by the formula:-A-OR₄ ; and a remaining group or groups are each independentlyrepresent a hydrogen atom, a cyano group, a lower alkyl group which maybe substituted by a halogen atom, a carbamoyl group which may besubstituted by a lower alkyl group, a cycloalkyl group, or a carboxylgroup which may be substituted by a protective group or an eliminatablegroup which is easily hydrolyzable in a human body, and also when R₉ is-A-OR₄, R₂ and R₃ may be combined with each other to form an alkylenegroup having 3 to 4 carbon atom.

In the above, as the lower alkyl group which may be substituted by ahalogen atom, there may be mentioned, for example, a methyl group, anethyl group, an n- or isopropyl group, a monofluoromethyl group, adifluoromethyl group, a trifluoromethyl group, a monofluoroethyl group,a difluoroethyl group, a trifluoroethyl group, etc. As the carbamoylgroup which may be substituted by a lower alkyl group, there may bementioned, for example, a carbamoyl group, a methylcarbamoyl group, adimethylcarbamoyl group, a 1-pyrrolidinylcarbonyl group, etc. As thecycloalkyl group, there may be mentioned, for example, a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.The protective group and the eliminatable group in the carboxyl groupwhich may be substituted by a protective group or an eliminatable groupwhich is easily hydrolyzable in a human body have the same meanings asdefined in the M previously mentioned. As the alkylene group having 3 to4 carbon atoms, there may be mentioned, for example, a propylene group,a butylene group, etc.

Explanation of R₄

R₄ is a hydrogen atom or a lower alkyl group.

In the above, as the lower alkyl group, there may be mentioned astraight or branched alkyl group having 1 to 3 carbon atoms. Forexample, a methyl group, an ethyl group, an n- or iso-propyl group, etc.may be mentioned.

Explanation of A

A is a straight or branched lower alkylene group having 1 to 6 carbonatoms. As such alkylene groups, there may be mentioned, for example, amethylene group, an ethylene group, a trimethylene group, atetramethylene group, a methylethylene group, an ethylethylene group, anethylidene group, etc.

In the above formula (I), as the specific examples of the grouprepresented by the following formula (a): ##STR9## there may bementioned, for example, the following groups.(2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(5-carbamoyl-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-hydroxymethyl-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-hydroxymethyl-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thio,

(2-hydroxymethyl-5-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(6-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(6-carbamoyl-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-hydroxymethyl-5-monofluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-hydroxymethyl-5,6,7,8-tetrahydro-s-triazolo[5,1-b]quinazolin-9-yl)thio,

[2-(1-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[2-(1-hydroxyethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[5-carboxy-2-(1-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[5-carbamoyl-2-(1-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin7-yl)thio,

[2-(1-hydroxyethyl)-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[2-(1-hydroxyethyl)-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl]thio,

[2-(1-hydroxyethyl)-5-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[6-carboxy-2-(1-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[6-carbamoyl-2-(1-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin7-yl)thio,

[2-(1-hydroxyethyl)-5-monofluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio

[2-(1-hydroxyethyl)-5,6,7,8-tetrahydro-s-triazolo[5,1-b]quinazolin-9-yl)thio,

[2-(2-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[2-(2-hydroxyethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[5-carboxy-2-(2-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[5-carbamoyl-2-(2-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin7-yl)thio,

[2-(2-hydroxyethyl)-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[2-(2-hydroxyethyl)-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl]thio,

[2-(2-hydroxyethyl)-5-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[6-carboxy-2-(2-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio,

[6-carbamoyl-2-(2-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin7-yl)thio,

[2-(2-hydroxyethyl)-5-monofluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio

[2-(2-hydroxyethyl)-5,6,7,8-tetrahydro-s-triazolo[5,1-b]quinazolin-9-yl)thio,

(2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(5-carboxy-2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(5-carbamoyl-2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-methoxymethyl-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin7-yl)thio,

(2-methoxymethyl-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thio,

(2-methoxymethyl-5-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(6-carboxy-2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(6-carbamoyl-2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-methoxymethyl-5-monofluoromethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2-methoxymethyl-5,6,7,8-tetrahydro-s-triazolo[5,1-b]quinazolin-9-yl)thio,

(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thio,

(5-hydroxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(3-hydroxymethyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(3-hydroxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(5-hydroxymethyl-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(3-hydroxymethyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(3-carboxy-5-hydroxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(3,5-bis(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl)thio,

(5-methoxymethyl-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(5-methoxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thio,

(7-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(7-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(7-hydroxymethyl-2-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(2,7-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(7-methoxymethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(7-methoxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(7-methoxymethyl-2-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(7-hydroxymethyl-2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thio,

(3-carboxy-7-hydroxymethylpyrazolo[1,5-a]pyrimidin-5-yl)thio, and

(3-carboxy-7-methoxymethylpyrazolo[1,5-a]pyrimidin-5-yl)thio.

As the pharmaceutically acceptable salts of the β-lactam compoundsaccording to the present invention, there may be mentioned alkali metalsalts such as of sodium salts, potassium salts, etc.; alkaline earthmetal salts such as of magnesium salts, calcium salts, etc.; ammoniumsalts; salts with organic bases such as of diisopropylamine,benzylamine, triethanolamine, triethylamine, N-methylmorpholine,pyridine, piperazine, etc.; salts with organic acids such as of aceticacid, formic acid, maleic acid, fumaric acid, methanesulfonic acid,p-toluenesulfonic acid, etc.; salts with inorganic acids such as ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andthe like.

Manufacturing methods of the novel β-lactam compounds

The novel β-lactam compounds to be intended in the present invention canbe synthesized according to the following four methods.

The first method

The title compound can be obtained by reacting the compound representedby the formula (II): ##STR10## (wherein symbols in the formula are thesame as mentioned above) with the carboxylic acid represented by theformula (III):

    R.sub.1 -OH                                                (III)

(wherein symbols in the formula are the same as mentioned above)

or its reactive derivative and then, if necessary, removing a protectivegroup.

The second method

The compound represented by the formula (I'): ##STR11## can be obtainedby reactin9 the compound represented by the formula (IV): ##STR12##(wherein symbols in the formula are the same as mentioned above) withthe compound represented by the formula (V): ##STR13## (wherein symbolsin the formula are the same as mentioned above) or its reactivederivative and then, if necessary, removing a protective group.

Also, the compound represented by the formula (I"): ##STR14## (whereinsymbols in the formula are the same as mentioned above) can be obtainedby reacting the above compound (IV) with the compound represented by theformula (V'): ##STR15## (wherein symbols in the formula are the same asmentioned above) or its reactive derivative and then, if necessary,removing a protective group.

In this method, the starting compound represented by the formula (IV) isa novel compound, and an example of the synthesizing method is shown byreferring reaction schemes in the following: ##STR16## (wherein R"' is aprotective group and the other symbols are the same as mentioned above).

The third method

The title compound can be obtained by reacting the compound representedby the formula (VI): ##STR17## wherein J represents a halogen atom or anacetoxy group and the other symbols are the same as mentioned above)

with the compound represented by the formula (VII):

    B-H                                                        (VII)

(wherein symbol in the formula is the same as mentioned above)

and then, if necessary, removing a protective group.

In this method, the starting compound represented by the formula (vII)is a novel compound, and an example of the synthesizing method is shownby referring reaction schemes in the following: ##STR18## (whereinsymbols in the formula are the same as mentioned above). ##STR19##(wherein R₁₁ represents a lower alkyl group and the other symbols in theformulae are the same as mentioned above).

The fourth method

The compound represented by the formula (I'): ##STR20## can be obtainedby reacting the compound represented by the formula (VIII): ##STR21##(wherein symbols in the formula are the same as mentioned above) withthe compound represented by the formula (IX): ##STR22## (wherein symbolsin the formula are the same as mentioned above) or a salt thereof, andremoving a protective group, if necessary.

In the present reaction, it is preferred to use a salt of the compoundof the formula (IX). As such a salt, there may preferably be used a saltwith a mineral acid such as hydrochloric acid, or an organicc sulfonicacid such as p-toluenesulfonic acid. Such an acid is preferably usedwith an equimolar or a slight excess amount. The present reaction ispreferably carried out in the presence of a polar solvent such asdimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrileor water, more preferably in dimethylacetamide. If the latter solvent isused, a syn-isomer of the final product can be obtained withparticularly good yield. The temperature of the present reaction ispreferably in the range of 0° C. to a room temperature.

In the following, producing methods of the novel β-lactam compoundsaccording to the present invention will be explained in more detail.

The first method

Specific examples of the compound represented by the formula (III) mayinclude, for example, the following compounds:

2-(2-Amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}aceticacid,

2-(2-Amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]ethoxyimino}aceticacid,

2-(2-Amino-1,3-thiazol-4-yl)-2-{[3-(3,4-dihydroxybenzoyl)carbazoyl]methoxyimino}aceticacid,

2-(2-Amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-diacetoxybenzoyl)carbazoyl]-1-methylethoxyimino}aceticacid,

2-(2-Amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-diacetoxybenzoyl)carbazoyl]ethoxyimino}aceticacid,

2-(2-Amino-1,3-thiazol-4-yl)-2-{[3-(3,4-diacetoxybenzoyl)carbazoyl]methoxyimino}aceticacid,

2-(2-Amino-1,3-thiazol-4-yl)acetic acid,

2-(2-Amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid,

2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid,

2-(2-Thienyl)acetic acid.

The reaction between the compound (II) and the compound (III) isdesirably carried out, in general, by using reactive derivatives of thecompound (III) as the compound (III). In this case, it is desired toprotect previously the hydroxyl group as an acyl ester. As the reactivederivatives, there may be mentioned, for example, acid halides, mixedacid anhydrides, active esters and the like. Further, while freecarboxylic acids can be used as such, suitable condensation reagent maydesirably be used in this case. As the reagent, there may be employed,for example, N,N'-dicyclohexylcarbodiimide (DCC),N,N'-carbonyldiimidazole, cyanuric chloride, Vilsmeier reagent and thelike. Such reactions have been known in the field of penicillinchemistry, cephalosporin chemistry and peptide chemistry. The equimolaramounts of the compounds (II) and (III) are employed in general. Thesereactions are usually carried out at -10° to 30° C. for about 0.5 to 2hours in a suitable solvent such as methylene chloride, chloroform,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide,acetonitrile, acetone, water or mixed solvents of the above. Treatmentsafter the reaction can be carried out by the methods well known in theart such as separation, purification and the like.

The second method

Specific examples of the compound represented by the formula (IV) mayinclude, for example, the following compounds:

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl-3-cephem-4-carboxylicacid

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-hydroxymethyl-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-hydroxymethyl-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-(1-hydroxyethyl)-striazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-(1-hydroxyethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-(1-hydroxyethyl)-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2-(1-hydroxyethyl)-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-carboxy-2-(1-hydroxyethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-hydroxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3-hydroxymethyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3-hydroxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-hydroxymethyl-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3-hydroxymethyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3-carboxy-5-hydroxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3,5-bis(hydroxymethyl)pyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-methoxymethyl-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(5-methoxymethylpyrazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-hydroxymethyl-2-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(2,7-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-methoxymethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-methoxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-methoxymethyl-2-trifluoromethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(7-hydroxymethyl-2-methoxymethyl-s-triazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3-carboxy-7-hydroxymethylpyrazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid, and

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-(1-hydrazinocarbonyl-1-methylethoxyimino)acetamido}-3-[(3-carboxy-7-methoxymethylpyrazolo[1,5-a]pyrimidin-5-yl)thiomethyl]-3-cephem-4-carboxylicacid.

The reaction of the compound (IV) and the compound (V) is carried out byallowing the latter as such or the hydroxyl group protected as an acylester to react as acid halides, mixed acid anhydrides or active esters,or suitable condensation reagents such as N,N'-dicyclohexylcarbodiimide(DCC), N,N'-carbonyldiimidazole, cyanuric chloride, Vilsmeier reagentand the like can be employed. These reactions can be carried out in asuitable solvent such as methylene chloride, chloroform,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide,actonitrile, acetone, water or mixed solvents of the above. at about-10° to 50° C. for about 0.5 to 2 hours. The equimolar amounts of thestarting compounds are employed in general.

The thus obtained compound (I) can be easily separated and purified bythe known method.

The third method

Specific examples of the compound represented by the formula (VI) mayinclude, for example, the following compounds:

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-acetoxymethyl-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)ethoxyimino]acetamido}-3-acetoxymethyl3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-[(3-(3,4-dihydroxybenzoyl)carbazoyl)methoxyimino]acetamido}-3-acetoxymethyl-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-chloromethyl-3-cephem-4-carboxylicacid,

7-552-[2-Amino-1,3-thiazol-4-yl]-2-[1-(3(3,4-dihydroxybenzoyl)carbazoyl)ethoxyimino]acetamido}-3-chloromethyl-3-cephem-4-carboxylicacid,

7-{2-[2-Amino-1,3-thiazol-4-yl]-2-[(3-(3,4-dihydroxybenzoyl)carbazoyl)methoxyimino]acetamido}-3-chloromethyl-3-cephem-4-carboxylicacid.

The compounds represented by the formula (VII) may include, for example,the following compounds:

2-Hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,2-Hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine,

5-Carboxy-2-hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-Hydroxymethyl-7-mercapto-5,6-dimethyl-s-triazolo[1,5-a]pyrimidine,

6-Carboxy-2-hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-Hydroxymethyl-5-monofluoromethyl-7-mercapto-s-triazolo1,5-a]pyrimidine,

2-Hydroxymethyl-6,7-dihydro-8-mercapto-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidine,

2-Hydroxymethyl-5,6,7,8-tetrahydro-9-mercapto-s-triazolo5,1-b]quinazoline,

2-(1-Hydroxyethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(1-Hydroxyethyl)-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine,

5-Carboxy-2-(1-hydroxyethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(1-Hydroxyethyl)-7-mercapto-5,6-dimethyl-s-triazolo[1,5a]pyrimidine,

6-Carboxy-2-(1-hydroxyethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(1-Hydroxyethyl)-5-monofluoromethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(1-Hydroxyethyl)-6,7-dihydro-8-mercapto-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidine,

2-(1-Hydroxyethyl)-5,6,7,8-tetrahydro-9-mercapto-s-triazolo[5,1-b]quinazoline,

2-(2-Hydroxyethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(2-Hydroxyethyl)-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine,

5-Carboxy-2-(2-hydroxyethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(2-Hydroxyethyl)-7-mercapto-5,6-dimethyl-s-triazolo[1,5a]pyrimidine,

6-Carboxy-2-(2-hydroxyethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(2-Hydroxyethyl)-5-monofluoromethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-(2-Hydroxyethyl)-6,7-dihydro-8-mercapto-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidine,

2-(2-Hydroxyethyl)-5,6,7,8-tetrahydro-9-mercapto-s-triazolo[5,1-b]quinazoline,

2-Methoxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

-Methoxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine,

5-Carboxy-2-methoxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-Methoxymethyl-7-mercapto-5,6-dimethyl-s-triazolo[1,5-a]pyrimidine,

6-Carboxy-2-methoxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

2-Methoxymethyl-5-monofluoromethyl-7-mercapto-s-triazolo-1,5-a]pyrimidine,

2-Methoxymethyl-6,7-dihydro-8-mercapto-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidine,

2-Methoxymethyl-5,6,7,8-tetrahydro-9-mercapto-s-triazolo-5,1-b]quinazoline.

5-Hydroxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine,

2,5-Bis(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine,

5-Methoxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine,

5-Methoxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine,

5-Methoxymethyl-7-mercapto-2-trifluoromethyl-s-triazolo-[1,5-a]pyrimidine,

2-Carboxy-5-methoxymethyl-7-mercapto-s-triazolo[1,5-a]-pyrimidine,

5-Hydroxymethyl-7-mercaptopyrazolo[1,5-a]pyrimidine,

3-Hydroxymethyl-7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine,

3-Hydroxymethyl-7-mercaptopyrazolo[1,5-a]pyrimidine,

5-Hydroxymethyl-7-mercapto-2-methylpyrazolo[1,5-a]pyrimidine,

3-Hydroxymethyl-7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine,

3-Carboxy-5-hydroxymethyl-7-mercaptopyrazolo[1,5-a]pyrimidine,

3,5-Bis(hydroxymethyl)-7-mercaptopyrazolo[1,5-a]pyrimidine,

7-Hydroxymethyl-5-mercapto-s-triazolo[1,5-a]pyrimidine,

7-Hydroxymethyl-5-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine,

7-Hydroxymethyl-5-mercapto-2-trifluoromethyl-s-triazolo-[1,5-a]pyrimidine,

2,7-Bis(hydroxymethyl)-5-mercapto-s-triazolo[1,5-a]pyrimidine,

5-Mercapto-7-methoxymethyl-s-triazolo[1,5-a]pyrimidine,

5-Mercapto-7-methoxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidine,

5-Mercapto-7-methoxymethyl-2-trifluoromethyl-s-triazolo-[1,5-a]pyrimidine,

7-Hydroxymethyl-5-mercapto-2-methoxymethyl-s-triazolo-[1,5-a]pyrimidine,

3-Carboxy-7-hydroxymethyl-5-mercaptopyrazolo[1,5-a]pyrimidine and

3-Carboxy-5-mercapto-7-methoxymethylpyrazolo[1,5-a]pyrimidine.

The reaction of the compound (VI) and the compound (VII) is, when --COOMis a free carboxylic acid or its salt, carried out by contacting them inwater or water and a water-soluble organic solvent such as acetone,methanol, ethanol, isopropanol, acetonitrile, etc. This reaction isdesirably carried out at around neutral of pH and the reaction systemcan be maintained at around neutral by properly adding alkalinecompounds such as an alkali hydroxide, an alkali carbonate, an alkalihydrogencarbonate, an alkali dihydrogenphosphate, an alkalimonohydrogenphosphate, etc. The reaction is generally carried out at atemperature of about 20° to 70° C. The terminal point of the reaction isconfirmed by a thin layer chromatography. The reaction time is about 0.5to 24 hours. Since the thus obtained compound (I) is being dissolved asa water-soluble alkali salt in a reaction mixture, adsorption,separation and purification treatments are carried out by usingadsorptive resins such as Diaion HP-20 (trade name, produced byMitsubishi Chemical Industries, Ltd.), Amberlite XAD II (trade name,produced by Rohm & Haas, Co.) etc.

In case of -COOM being ester, the reaction is carried out in an organicsolvent such as methanol, ethanol, isopropanol, tetrahydrofuran,acetonitrile, dimethylformamide and the like at 50° to 100° C. for 0.5to 3 hours.

In the present method, equimolar amounts of the compound (VI) and thecompound (VII) are generally employed, respectively.

Any protecting groups in an obtained compound, e.g. on phenolic hydroxyor amino, can be cleaved off; phenolic hydroxy protecting groups, e.g.as follows: acetyl with water at pH 7-8 or with ammonia, trimethylsilylwith ethanol or water, tetrahydropyranyl by acidic hydrolysis, e.g. withaqueous hydrochloric acid. Amino protecting groups can be cleaved off asfollows: amino protecting groups which are cleavable by acid arepreferably removed with the aid of a lower alkanecarboxylic acid whichis optionally halogenated. In particular, formic acid or trifluoroaceticacid is used. As a rule, the temperature is room temperature, althoughslightly elevated or slightly lowered temperature can be used, e.g. inthe range of about 0° C. to 40° C. protecting groups which are cleavableby alkali are generally hydrolyzed with dilute aqueous caustic alkali at0° C. to 30° C. The chloroacetyl, bromoacetyl and iodoacetyl protectinggroups can be cleaved off by means of thiourea in an acidic, neutral oralkaline medium at about 0°-30° C.

Any carboxy protecting groups can be cleaved off as follows: when theprotecting group represents a trimethylsilyl group, this group can beremoved especially readily by treatment with water or ethanol.Benzhydryl and t-butyl groups can be cleaved off with formic acid ortrifluoroacetic acid in the manner given above. Allyl groups areremoved, e.g. by means of palladium salts and tertiary amines such asN-methylpyrrolidine or N-methylmorpholine.

In the present invention, the compound (I) obtained by each methods of(1), (2), (3) and (4) as mentioned above can be converted into, ifnecessary, a pharmaceutically acceptable salt or an ester which iseasily hydrolyzed in a human body when the compound has a freecarboxylic acid.

For the manufacture of the readily hydrolyzable esters of the carboxylicacids of formula (I), the carboxylic acid is preferably with the iodide,containing the ester group. The reaction can be accelerated with the aidof a base, e.g. an alkali metal hydroxide or carbonate or an organicamine such as triethylamine. This reaction is preferably carried out inan inert organic solvent such as dimethylacetamide, hexamethylphosphoricacid triamide, dimethyl sulfoxide or, preferably, dimethylformamide. Thetemperature preferably lies in the range of about 0° to 40° C.

The manufacture of the salts and hydrates of the compounds of formula(I) or of the hydrates of these salts can be effected in a manner knownper se, e.g. by reacting the carboxylic acid of formula (I) with anequivalent amount of the desired base, conventionally in a solvent suchas water or in an organic solvent such as ethanol, methanol, acetone ormany others. Corresponding salt formation is brought about by theaddition of an organic or inorganic acid. The temperature of the saltformation is not critical. It generally lies at room temperature, butcan also be slightly thereover or thereunder, for example, in the rangeof 0° C. to +50° C. The β-lactam compound according to the presentinvention can be administrated orally or non-orally to human beings oranimals by various known administrating method.

Further, said compounds are used singly or by formulating withauxiliaries, liquid diluents, binders, lubricants, humectants, etc.,which are pharmaceutically acceptable in general, for example, in theform of general medicinal compositions such as tablets, granulars, sugarcoatings tablets, powders, capsules, gels, dry syrups, syrups, amples,suspensions, liquids, emulsions, ointments, pastes, creams,suppositories, etc.

Moreover, as the other additives which can be formulated, there may bementioned dissolution delaying agents, adsorption accelerating agents,surface active agents, etc. Any way, any forms which arepharmaceutically acceptable can be employed.

The β-lactam compound according to the present invention can be used asalone or mixture of two or more different kinds of derivatives and theamount of the compounds is about 0.1 to 99.5 %, preferably 0.5 to 95 %based on the weight of the all medicinal composition.

The medicinal composition containing the compound of the presentinvention can be formulated with an other compounds which arepharmaceutically active as effective ingredients other than saidcompound or mixtures thereof.

A dosage per day to a patient of the novel β-lactam compound accordingto the present invention may be varied depending upon an individual man,kinds of animals, weights thereof and a state to be remedied, butgenerally is in the range of 1 to 1000 mg per 1 kg of weight, preferablyabout 10 to 800 mg.

According to the present invention, a novel β-lactam compound can beprovided. The compound represented by the formula (I) of the presentinvention shows excellent antibacterial activity against a wide range ofpathogenic bacteria such as gram negative bacteria and gram positivebacteria.

Accordingly, the β-lactam compound according to the present inventioncan be effectively utilized for the sake of prevention or remedy ofdiseases due to the aforesaid pathogenic bacteria in human beings oranimals.

EXAMPLES

In the following, the present invention is explained in detail byreferring to Examples.

EXAMPLE 1

Synthesis of2-hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

(1) Synthesis of 3-amino-5-hydroxymethyl-s-triazole

While stirring 1738 g (16 moles) of a 70 % glycolic acid, 1088 g (8moles) of aminoguanidino-carboxylic acid was added thereto with littleby little. To the mixture was added 8 ml of conc. nitric acid and themixture was stirred under reflux for 24 hours. The reaction mixture wasice-cooled, and then precipitates were collected by filtration, washedwith water and then dried.

Yield: 760 g

¹ H NMR (d6-DMSO) 6: 3.74 (s, 2H). (2) Synthesis of7-hydroxy-2-hydroxymethyl-5-methyl-striazolo[1,5-a]pyrimidine After amixture of 750 g of the compound obtained in (1), 3.5 iters of methylacetoacetate and 75 ml of acetic acid was stirred at 100° C. for 24hours, it was allowed to cool overnight and precipitated crystals werecollected by filtration, washed with ethanol and dried.

Yield: 680 g

¹ H NMR (d₆ -DMSO) 6:

2.35 (s, 3H), 4.60 (s, 2H), 5.88 (s, ¹ H).

(3) Synthesis of2-acetoxymethyl-7-hydroxy-5-methyl-striazolo[1,5-a]pyrimidine

A mixture of 520 g of the compound obtained in (2), 3 liters of DMF, 2liters of acetic anhydride and 40 g of p-toluenesulfonic acid wasstirred at 60° C. for 24 hours. The reaction mixture was condensed. Tothe residue precipitated crystals was added 4 liters of ether and themixture was stirred, filtered and crystals obtained were dried.

Yield: 692 g

These crystals were recrystallized from 6 liters of methanol.

Yield: 297 g

¹ H NMR (d₆ -DMSO) δ:

2.17 (s, 3H), 2.38 (s, 3H), 5.27 (s, 2H), 5.95 (s, 1H).

(4) Synthesis of2-acetoxymethyl-7-chloro-5-methyl-s-triazolo[1,5-a]pyrimidine

Phosphorus oxychloride (900 ml) was stirred under ice-cooling, and 200ml of N,N-dimethylaniline was added dropwise thereto. To the mixture wasadded 173 g (0.78 mole) of the compound and the mixture was stirred at55° to 60° C. for an hour. After removal of phosphorus oxychloride fromthe reaction mixture, the reaction mixture was dissolved in 2 liters ofchloroform, and after adding crushed ice and water thereto, it wasstirred. Subsequently, the reaction mixture was immediately transferredto a separating funnel, and a chloroform layer was obtained. Thechloroform layer was washed three times with water and dried overanhydrous magnesium sulfate, and then condensed. To the residuecrystallized was added one liter of isopropylether, rnd then the mixturewas stirred and crystals were collected by filtration and dried.

Yield: 186 g

¹ H NMR (d₆ -DMSO) δ:

2.22 (s, 3H), 2.80 (s, 3H), 5.48 (s, 2H), 7.53 (s, ¹ H).

(5) Synthesis of2-hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

In 400 ml of ethanol was dissolved 23.7 g of2-acetoxymethyl-7-chloro-5-methyl-s-triazolo[1,5-a]pyrimidine, and 19 gof thiourea was added thereto and the mixture was stirred for 30 minutesunder reflux. The reaction mixture was ice-cooled and the precipitatedcrystals were collected by filtration, washed with ethanol and dried.After the obtained crystals were dissolved in a 10 % potassium hydroxideaqueous solution and stirred for 30 minutes, pH was adjusted to 2 withaddition of a 2N hydrochloric acid. The precipitated crystals werecollected by filtration, washed with water and dried to obtain 15.3 g ofthe title compound.

¹ H NMR (d₆ -DMSO) δ:

2.39 (s, 3H), 4.68 (s, 2H), 6.95 (s, 1H).

EXAMPLE 2

Synthesis of7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

In 130 ml of acetonitrile were suspended 11.08 g of2-hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine and15.38 g of 7-aminocephalosporanic acid, and 24.6 ml of borontrifluoride - ethyl ether complex was added thereto and the mixture wasstirred at 50° C. for 2 hours. After the reaction mixture wasice-cooled, 300 ml of water was added thereto and pH thereof wasadjusted to 2 with conc. aqueous ammonia. The precipitated crystals werecollected by filtration, washed with water and with acetone, and thendried to obtain 18.5 of the title compound.

¹ H NMR (CF₃ COOD) δ:

2.93 (s, 3H), 3.93 (s, 2H), 4.88 (AB_(q), 2H), 5.43 (s, 2H), 5.54 (s,2H), 7.85 (s, 1H).

EXAMPLES 3 to 5

In the same manner as in Example 2, the following compounds weresynthesized.

EXAMPLE 3

7-Amino-3-[(2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

¹ H NMR (CF₃ COOD) δ:

3.92 (s, 2H), 4.85 (AB_(q), 2H), 5.38 (s, 2H), 5.51 (s,

2H), 7.97 (d, J=6Hz, 1H), 9.15 (d, J=6Hz, 1H).

EXAMPLE 4

7-Amino-3-[(2-hydroxymethyl-5,6-dimethyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

1H NMR (CF₃ COOD) δ:

2.33 (s, 3H), 2.47 (s, 3H), 3.77 (s, 2H), 4.67 (AB_(q), 2H), 5.36 (s,2H), 5.48 (s, 2H).

EXAMPLE 57-Amino-3-[(2-hydroxymethyl-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thiomethyl]-3-cephem-4-carboxylicacid

¹ H NMR (CF₃ COOD)δ:

2.33 (s, 3H), 2.47 (s, 3H), 3.77 (s, 2H), 4.67 (AB_(q),

2H), 5.36 (s, 2H), 5.48 (s, 2H).

EXAMPLE 6

Synthesis of diphenylmethyl7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In a suspension of 17.48 g of7-amino-3-[(2-hydroxymethyl5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid in 100 ml of methanol and 300 ml of methylene chloride was addeddropwise diphenyldiazomethane as 50 ml of a methylene chloride solution,synthesized from 23.55 g of benzophenonehydrazone, 26 g of mercuricoxide (yellow) and 200 ml of n-hexane while stirring, and the mixturewas stirred at room temperature overnight. After the reaction mixturewas condensed, ether was added thereto to effect crystallization. Thecrystals thus formed were collected by filtration and dried to obtain30.15 g of the title compound. ¹ H NMR (d₆ -DMSO+CDCl₃) δ:

2.58 (s, 3H), 3.75 (bs, 2H), 4.33 (bs, 2H), 4.87 (s, 2H), 4.90 to 5.22(m, 2H), 6.97 to 7.70 (m, 12H).

EXAMPLES 7 to 9

In the same manner as in Example 6, the following compounds weresynthesized.

EXAMPLE 7

Diphenylmethyl7-amino-3-[(2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

¹ H NMR (d₆ -DMSO+CDCl₃) δ:

3.77 (s, 2H), 4.32 (bs, 2H), 4.84 (s, 2H), 4.92 to 5.26 (m, 2H), 6.95 to7.78 (m, 12H), 8.85 (d, J=6Hz, 1H).

EXAMPLE 8

Diphenylmethyl7-amino-3-[(2-hydroxymethyl-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

¹ H NMR (d₆ -DMSO+CDCl₃) δ:

2.42 (s, 3H), 2.63 (s, 3H), 3.76 (s, 2H), 4.36 (bs, 2H), 4.88 (s, 2H),4.88 to 5.23 (m, 2H), 6.87 to 7.68 (m, 11H).

EXAMPLE 9

Diphenylmethyl7-amino-3-[(2-hydroxymethyl-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thiomethyl]3-cephem-4-carboxylate

¹ H NMR (d₆ -DMSO+CDCl₃) δ: 2.26 to 2.80 (m, 2H), 3.18 to 3.60 (m, 4H),3.92 (s, 2H), 4.88 (AB_(q), 2H), 5.44 (s, 2H), 5.53 (s, 2H).

EXAMPLE 10

Synthesis of7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

In 40 ml of DMF were dissolved 6.44 g of2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}acetic acid.hydrochloride, 12.2 g of diphenylmethyl7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateobtained in Example 6 and 2.6 g of 1-hydroxybenzotriazole, and thesolution was ice-cooled. To the solution was added of 3.5 g of DCC, andthe mixture was stirred for 15 minutes under ice-cooling and furtherstirred at room temperature for one hour. After the reaction mixture wasfiltered, 30 ml of chloroform was added to the filtrate and the mixturewas added dropwise into 40 liters of ether. After precipitates werecollected by filtration and washed with ether, a powder obtained bydrying was purified through silica gel column to obtain powder. A mixedsolution of 60 ml of trifluoroacetic acid and 15 ml of anisole wasice-cooled, and the powder obtained previously was added thereto,followed by stirring for 30 minutes. The resulting mixture was addeddropwise into 500 ml of ether, and precipitates formed was collected byfiltration, washed with ether and dried to obtain 7.82 g of the titlecompound.

¹ H NMR (d₆ -DMSO) δ: 1.60 (s, 6H), 2.62 (s, 3H), 3.80 (bs, 2H), 4.52(bs, 2H), 4.70 (s, 2H), 5.32 (d, J=5Hz, 1H), 5.82 to 6.18 (m, 1H), 6.83to 7.52 (m, 5H).

EXAMPLES 11 to 18

In the same manner as in Example 10, the following compounds weresynthesized.

EXAMPLE 117-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxy-benzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 1.59 (s, 6H), 3.78 (bs, 2H), 4.52 (bs, 2H), 4.68(s, 2H), 5.35 (d, J=5Hz, 1H), 5.82 to 6.15 (m, 1H), 6.81 to 7.53 (m,5H), 8.88 (d, J=5Hz, 1H).

Example 12

7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 1.60 (s, 6H), 2.51 (s, 3H), 2.62 (s, 3H), 3.78 (s,2H), 4.48 (bs, 2H), 4.68 (s, 2H), 5.28 (d, J=4.5Hz, 1H), 5.78 to 6.20(m, 1H), 6.82 to 7.60 (m, b 4H).

Example 13

7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyiminc]acetamido}-3-[(2-hydroxymethyl-6,7-dihydro-5H-cyclopenta[d]-s-triazolo[1,5-a]pyrimidin-8-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 1.62 (s, 6H), 2.02 to 2.50 (m, 2H), 2.90 to 3.44(m, 4H), 3.81 (s, 2H), 4.48 (bs, 2H), 4.70 (s, 2H), 5.30 (d, J=5Hz, 1H),5.80 to 6.14 (m, 1H), 6.83 to 7.66 (m, 4H).

Example 14

7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)methylethoxyimino]acetamido}-3-[2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 2.60 (s, 3H), 3.78 (s, 2H), 4.48 (bs, 2H), 4.66(s, 2H), 5.28 (d, J=5Hz, 1H), 5.78 to 6.15 (m, 1H), 6.78 to 7.48 (m,5H).

Example 15

7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)ethoxyimino]acetamido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 1.50 (s, 3H), 2.62 (s, 3H), 3.77 (bs, 2H), 4.50(bs, 2H), 4.68 to 4.83 (m, 3H), 5.22 (d, J=5Hz, 1H), 5.62 to 5.98 (m,1H), 6.58 to 7.48 (m, 5H).

Example 16

7-[2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 2.68 (s, 3H), 3.72 to 4.02 (m, 4H), 4.58 (bs, 2H),4.70 (s, 2H), 5.38 (d, J=5Hz, 1H), 5.74 to 6.08 (m, 1H), 7.24 (s, 1H),7.58 (s, 1H).

Example 17

7-[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetamido]3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 2.63 (s, 3H), 3.82 (s, 2H), 4.58 (bs, 2H), 4.72(s, 2H), 5.35 (d, J=4Hz, 1H), 5.74 to 6.06 (m, 1H), 7.23 (s, 1H), 7.62(s, 1H).

Example 18

7-[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

¹ H NMR (d₆ -DMSO) δ: 2.60 (s, 3H), 3.84 (s, 2H), 4.03 (s, 3H), 4.58(bs, 1H), 4.70 (s, 2H), 5.37 (d, J=4Hz, 1H), 5.82 to 6.12 (m, 1H), 7.18(s, 1H), 7.54 (s, 1H).

Example 19

Synthesis of7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamide}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.sodium salt

In 200 ml of water was suspended 7.7 g of7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride, and a 5% sodium hydrogen carbonate solution wasadded thereto to dissolve at a pH 7. After the resulting solution wasadsorbed to 500 ml of HP 20 column filled with water, it was washed withwater. Subsequently, the mixture was eluted with a 50% methanol - water.After evaporation of methanol, the residue was freeze-dried to obtain5.3 g of the title sodium salt compound.

Example 20

Synthesis of7-[2-(2-thienyl)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

In 100 ml of water was suspended 4.6 g of7-amino-3-(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-yl)thiomethyl]-3-cephem-4-carboxylicacid obtained in Example 2, and a 2N aqueous sodium hydroxide solutionwas added to the suspension and the mixture was dissolved at a pH 7. Tothis solution was while stirring under ice-cooling added dropwise asolution of 1.93 g of 2-thienyl acetyl chloride in 20 ml of ether overone hour. During this time, a pH of the mixture was maintained to 7 to7.5 by addition of a 2N aqueous sodium hydroxide. After stirring forfurther one hour, the reaction mixture was washed with ethyl acetate.The reaction mixture was adjusted to pH 2.5 with a 2N hydrochloric acidunder ice-cooling and stirring, and precipitated crystals were collectedby filtration, washed with water and dried to obtain 4.81 g of the titlecompound.

¹ H NMR (d₆ -DMSO) δ: 2.65 (s, 3H), 3.68 to 4.04 (m, 4H), 4.54 (bs, 2H),4.70 (s, 2H), 5.36 (d, J=5Hz, 1H), 5.68 to 6.12 (m, 1H), 7.08 to 7.28(m, 3H), 7.50 to 7.70 (m, 1H).

Example 21

Synthesis of7-[2-(2-amino-1,3-thiazol-4-yl)-2-(1-carboxy-methylethoxyimino)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid In 150 ml of THF were dissolved 7.26 g of2-(1-t-butoxycarbonyl-1-methylethoxyimino)-2-(2-tritylamino-1,3-thiazol-4-yl)aceticacid, 9.58 g of diphenylmethyl7-amino-3-[(2-hydroxymethyl-5-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateobtained in Example 6 and 2.3 g of 1-hydroxybenzotriazole and thesolution was ice-cooled. To the solution was added 3.09 g of DCC and themixture was stirred under ice-cooling for 30 minutes, and furtherstirred at room temperature for 22 hours. After filtration of thereaction mixture, 300 ml of ethyl acetate was added to the filtrate,washed sucessively with a 2N hydrochloric acid, water, a 5% aqueoussodium hydrogen carbonate solution, water and a saturated salinesolution, and dried over anhydrous magnesium sulfate. After evaporationof the solvent, the resulting oily product was purified through silicagel column to obtain 12 g of an oily product. This oily product wasdissolved in 80 ml of anisole and the solution was ice-cooled. To thesolution was added 80 ml of trifluoroacetic acid and the mixture wasstirred at room temperature for 2.5 hours. The reaction mixture wasadded dropwise into 1.8 liters of ether, and precipitated material wascollected by filtration and dried to obtain 4.5 g of the title compound.

¹ H NMR (d6-DMSO) δ: 1.56 (s, 6H), 2.66 (s, 3H), 3.83 (bs, 2H), 4.54(bs, 2H), 4.75 (s, 2H), 5.38 (d, J=5Hz, 1H), 5.81 to 6.14 (m, 1H), 7.18(s, 1H), 7.45 (s, 1H).

Example 22

Synthesis of7-mercapto-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

(1) Synthesis of7-hydroxy-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

A mixture of 90 g of methoxy acetic acid, 68 g of aminoguanidinebicarbonate, 40 ml of water and 0.5 ml of conc. nitric acid was stirredunder reflux for 24 hours, and then condensed. To the resulting residuewere added 250 ml of methyl acetoacetate and 5 ml of acetic acid and themixture was stirred in a bath of 100° to 120 ° C. After 4 hours, themixture was cooled by allowing to stand and crystals were collected byfiltration, washed with isopropanol and dried to obtain 82 g of thetitle compound.

¹ H NMR (d₆ -DMSO) δ: 2.40 (s, 3H), 3.43 (s, 3H), 4.57 (s, 2H), 5.92 (s,1H).

(2) Synthesis of7-chloro-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

To a mixed solution of 300 ml of phosphorus oxychloride and 50 ml ofN,N-dimethylaniline was added 38.8 g of pyrimidine, and the mixture wasstirred at 50° to 60° C. for one hour. After removing phosphorusoxychloride, the residue was dissolved in 500 ml of chloroform andstirred by adding ice. The chloroform layer was separated and washedwith water, and then dried over anhydrous magnesium sulfate anddistilled the solvent to obtain crystals. The crystals were collected byfiltration and washed with water, and then dried to obtain the titlecompound.

¹ H NMR (CDCl₃) δ: 2.76 (s, 3H), 3.62 (s, 3H), 4.85 (s, 2H), 7.25 (s,1H).

(3) Synthesis of7-mercapto-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

In 350 ml of water was dissolved 24 g of sodium hydrosulfide and 34.5 gof 7-chloro-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine wasadded thereto, and the mixture was stirred at 55° C. for one hour. Afterthe reaction mixture was filtered, it was ice-cooled and adjusted to pH1 with addition of a 2N-hydrochloric acid. The precipitates werecollected by filtration, washed with water and with isopropanol, anddried to obtain 30.18 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 2.38 (s, 3H), 3.44 (s, 3H), 4.65 (s, 2H), 6.97 (s,1H).

Example 23

Synthesis of7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

In 600 ml of acetonitrile were suspended 30.1 g of7-mercapto-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine and 38.9g of 7-aminocephalosporanic acid and 68.7 ml of boron trifluoride -ethyl ether complex was added thereto, and the mixture was stirred atroom temperature for 6 hours. One liter of water was added to thereaction mixture and the mixture was adjusted to pH 2 with addition of aconc. aqueous ammonia. The precipitated crystals were collected byfiltration, washed with water and with acetone, and then dried to obtain30 g of the title compound.

¹ H NMR (CF₃ COOD) δ: 2.87 (s, 3H), 3.70 (s, 3H), 3.86 (s, 2H), 4.78(AB_(q), 2H), 5.24 to 5.68 (m, 4H).

Example 24

Synthesis of diphenylmethyl7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

To a suspension comprising 30 g of7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid, 170 ml of methanol and 510 ml of methylene chloride was addeddropwise while stirring diphenyldiazomethane, which had been synthesizedfrom 39.25 g of benzophenonehydrazone, 43.22 g of mercuric oxide(yellow) and 350 ml of n-hexane, in 50 ml of methylene chloride, and themixture was stirred at room temperature overnight. After the reactionmixture was condensed and ether was added thereto to effectcrystallization. The crystals were collected by filtration and dried,and the resulting powder was purified through silica gel columnchromatography to obtain 31.1 g of the title compound.

¹ H NMR (CDCl₃) δ: 2.52 (s, 3H), 3.56 (s, 3H), 3.69 (s, 2H), 4.25 (s,2H), 4.72 to 5.08 (m, 4H), 6.70 (s, 1H), 7.04 (s, 1H), 7.17 to 7.63 (m,10H).

Example 25

Synthesis of7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochlride

In 50 ml of DMF were dissolved 4.6 g of2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}acetic acid.hydrochloride, 7.65 g of diphenylmethyl7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateobtained in Example 24 and 1.84 g of 1-hydroxybenzotriazole, and thesolution was ice-cooled. To the solution was added 2.5 g of DCC and themixture was stirred for 15 minutes while ice-cooling and further stirredat room temperature for an hour. After the reaction mixture wasfiltered, 30 ml of chloroform was added to the filtrate and the mixturewas added dropwise into 2 liters of ether. Precipitates were collectedby filtration, washed with ether and then dried, and the powder thusobtained was purified through silica gel column chromatography to obtainpowder.

A mixed solution of 20 ml of methylene chloride, 40 ml oftrifluoroacetic acid and 10 ml of anisole was ice-cooled and the powderpreviously obtained was added to the solution, and the mixture wasstirred for 30 minutes. Then, the mixture was added dropwise into 800 mlof ether, precipitates were collected by filtration, washed with etherand dried to obtain 5.9 g of the title compound.

¹ H NMR (CDCl₃) δ: 1.60 (s, 6H), 2.65 (s, 3H), 3.45 (s, 3H), 3.88 (bs,2H), 4.48 to 4.83 (m, 4H), 5.40 (d, J=5Hz, 1H), 5.88 to 6.24 (m, 1H),6.82 to 7.68 (m, 5H).

Example 26

Synthesis of sodium7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-5-meth.1-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

(1) Synthesis of 7-(2-amino-1,3-thiazol-4-ylglyoxylamido)-3-[(2-hydroxymethyl-5-methyl-s-triazclo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

To 20 ml of DMF was added 1.73 ml of phosphorus oxychloride and themixture was stirred at 40° C. for 30 minutes. This mixture was cooled to-20° C. and 1.9 g of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid,and the mixture was stirred at 0° C. for 3 hours.

After a mixed solution of 3.9 g of7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid, 7.5 ml of N,O-bis(trimethylsilyl)acetamide and 50 ml of methylenechloride was stirred at room temperature for 2 hours, the solution wascooled to -30° C. To the solution was added the previously obtainedmixture, and the mixture was stirred at -30° C. for 2 hours. Thereaction mixture was poured into 200 ml of ice-cold water andprecipitated crystals were collected by filtration, washed with waterand dried to obtain 1 g or powder.

Methanol (15 ml) was ice-cooled and 0.23 ml of phosphorus oxychloridewas added thereto. Then, 1 g of the powder obtained above was added tothe mixture and the mixture was stirred for 3 hours. The reactionmixture was added dropwise into 250 ml of ether, and precipitatedcrystals were collected by filtration, washed with water and dried toobtain 0.77 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 2.64 (s, 3H), 3.86 (bs, 2H), 4.62 (bs, 2H), 4.75(s, 2H), 5.36 (d, J=5Hz, 1H), 5.72 to 6.12 (m, 1H), 7.45 (s, 1H), 8.40(s, 1H).

(2) Synthesis of7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acet-amido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.sodium salt

In 10 ml of dimethylacetamide were dissolved 0.6 g of7-(2-amino-1,3-thiazol-4-ylglyoxylamido)-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride and 0.54 g of1-(2-aminoxy-2-methylpropionyl)-2-(3,4-dihydroxybenzoyl)hydrazine.hydrochlorideand the mixture was stirred at room temperature for one day. Thereaction mixture was condensed to a quarter and this was added dropwisein 30 ml of water. After pH was adjusted to 2, precipitating crystalswere collected by filtration and washed with water, and then they weresuspended in 20 ml of water and dissolved at pH 7 by adding a 5% sodiumhydrogen carbonate solution. After this was adsorbed to a 50 ml of HP 20column filled with water, this was eluted with a mixed solution ofmethanol and water, and then fractions containing the desired compoundwere condensed and freeze-dried to obtain 0.34 g of the title compound.

This has the same physical properties as those obtained in Example 19.

Example 27

Synthesis of sodium7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl-3-cephem-4-carboxylate

In 50 ml of DMF were dissolved 2.29 g of2-(2-formylamino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid, 7.65 g ofdiphenylmethyl7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-3-cephem-4-carboxylateand 1.84 g of 1-hydroxybenzotriazole and the solution was ice-cooled. Tothe solution was added 2.5 g of DCC and the mixture was stirred for 15minutes under ice-cooling and further stirred for one hour at roomtemperature. After filtration of the reaction mixture, 30 ml ofchloroform was added to the filtrate and the mixture was added dropwiseinto 2 liters of ether, and precipitates were collected by filtration,washed with ether and dried to obtain powder.

To 80 ml of ice-cooled methanol was added dropwise 1.57 ml of phosphorusoxychloride, and the powder obtained above was added to the mixture andthe mixture was stirred for 1.5 hours under ice-cooling. This reactionmixture was added dropwise into 1 liter of ether and precipitates werecollected by filtration, washed with ether and then powder obtained bydryness was purified through silica gel column to obtain powder.

This powder was dissolved in 20 ml of methylene chloride, and 10 ml ofanisole was added thereto and then 40 ml of trifluoroacetic acid wasadded thereto under ice-cooling and the mixture was stirred for 30minutes. This mixture was added dropwise into 1 liter of ether andprecipitates were collected by filtration, washed with ether and driedto obtain powder.

This powder was suspended in 100 ml of water, and dissolved by adding a5% sodium hydrogen cabonate solution at pH 7. Then, this solution wasadsorbed to a column of which 200 ml of HP 20 was filled with water,washed with water and then eluted with a methanol-water mixed solution.After condensing fractions containing the title compound, freeze-driedto obtain 2.96 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 2.60 (s, 3H), 3.41 (s, 3H), 3.78 (bs, 2H), 3.96(s, 3H), 4.46 (bs, 2H), 4.63 (s, 2H), 5.25 (d, J=5Hz, 1H), 5.72 to 6.05(m, 1H), 6.92 (s, 1H), 7.34 (s, 1H).

Example 28

Synthesis of5-carboxy-2-hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine

(1) Synthesis of7-hydroxy-2-hydroxymethyl-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

In 1.7 liters of methanol was suspended 60 g of3-amino-5-hydroxymethyl-1,2,4-triazole and 75 ml of dimethylacetylenedicarboxylate was added to the suspension, and the mixture wasstirred at 30° C. for 20 hours. Precipitates were collected byfiltration, washed with methanol and then dried to obtain 25.7 g of thetitle compound.

¹ H NMR (d₆ -DMSO) δ: 3.96 (s, 3H), 4.70 (s, 2H), 6.57 (s, 1H). (2)Synthesis of2-acetoxymethyl-7-hydroxy-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

A mixture of 25.7 g of7-hydroxy-2-hydroxymethyl-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine,200 ml of DMF, 47 ml of acetic anhydride and 1 g of p-toluenesulfonicacid was stirred at 60° C. for 24 hours. The reaction mixture wascondensed and 100 ml of methanol was added to the crystals precipitatedresidue, and the mixture was stirred. Then, crystals were collected byfiltration, washed with methanol and dried to obtain 8.9 g of the titlecompound.

¹ H NMR (d₆ -DMSO) δ: 2.18 (s, 3H), 4.05 (s, 3H), 5.33 (s, 2H), 6.67 (s,1H).

(3) Synthesis of2-acetoxymethyl-7-chloro-5-methoxycarbonyl-s-triazolor[1,5-a]pyrimidine

To a mixed solution of 30 ml of phosphorus oxychloride and 5.1 ml ofN,N-dimethylaniline was added 5.32 g of2-acetoxymethyl-7-hydroxy-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidineand the mixture was stirred at 50° C. for 1.5 hours, and then phosphorusoxychloride was removed. The residue was dissolved in 100 ml ofchloroform and after addition of ice, the mixture was stirred. Thechloroform layer was separated, washed with water and dried overanhydrous magnesium sulfate. The solvent was removed to obtain 5.75 g ofthe title compound as crystals.

¹ H NMR (d₆ -CDCl₃) δ: 2.25 (s, 3H), 4.18 (s, 3H), 5.58 (s, 2H), 8.20(s, 1H).

(4) Synthesis of5-carboxy-2-hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine

In 200 ml of ethanol was dissolved 12 g of2-acetoxymethyl-7-chloro-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidineunder heating, and 8.36 g of thiourea was added to the solution and themixture was stirred under reflux for 10 minutes. After cooling byallowed to stand, precipitates were collected by filteration, washedwith ethanol and then dissolved in 100 ml of a 10% KOH, and the solutionwas stirred at room temperature for one hour. This solution was adjustedto pH 1 with 2N HCl under ice-cooling and stirring, and precipitateswere ccllected by filtration, washed with water and then dried to obtain8.13 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 4.86 (s, 2H), 7.67 (s, 1H).

Example 29

Synthesis of7-amino-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

In 130 ml of acetonitrile were suspended 8 g of5-carboxy-2-hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine and9.53 g of 7-aminocephalosporanic acid and 17 ml of boron trifluoride -ethyl ether complex was added thereto, and the mixture was stirred atroom temperature for 5 hours. To the reaction mixture was added 300 mlof water and the mixture was adjusted to pH 2 with conc. aqueousammonia. Precipitated crystals were collected by filtration, washed withwater and with acetone, and dried to obtain 10.1 g of the titlecompound.

¹ H NMR (CF₃ COOD) δ: 3.85 (s, 2H), 4.98 (broad s, 2H, 5.42 (broad s,4H), 8.73 (s, 1H).

Example 30

Synthesis of diphenylmethyl7-amino-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

To a suspension of 10 g of7-amino-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-3-cephem-4-carboxylicacid, 100 ml of methanol and 300 ml of methylene chloride was addeddropwise while stirring diphenyldiazomethane, which had been synthesizedfrom 19.6 g of benzophenonehydrazone, 21.6 g of mercuric oxide (yellow)and 150 ml of n-hexane, in 30 ml of methylene chloride, and the mixturewas stirred at room temperature overnight. After the reaction mixturewas condensed and ether was added thereto to effect crystallization. Thecrystals were collected by filtration and dried to obtain 13.9 g of thetitle compound.

¹ H NMR (CDCl₃) δ: 3.72 (broad s, 2H), 4.38 (broad s, 2H), 4.78 to 5.16(m, 4H), 6.98 to 8.07 (m, 12H).

Example 31

Synthesis of7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid.hydrochloride

In 40 ml of DMF were dissolved 3.22 g of2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}aceticacid.hydrochloride, 6.5 g of diphenylmethyl7-amino-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateand 1.27 g of 1-hydroxybenzotriazole, and the solution was ice-cooled.To the solution was added 1.73 g of DCC and the mixture was stirred for15 minutes while ice-cooling and further stirred at room temperature for45 minutes. After the reaction mixture was filtered, 20 ml of chloroformwas added to the filtrate and the mixture was added dropwise into 2liters of ether. Precipitates were collected by filtration, washed withether and then dried, and the powder thus obtained was purified throughsilica gel column chromatography to obtain powder.

A mixed solution of 15 ml of methylene chloride, 30 ml oftrifluoroacetic acid and 8 ml of anisole was ice-cooled and the powderpreviously obtained was added to the solution, and the mixture wasstirred for 30 minutes. Then, the mixture was added dropwise into 500 mlof ether, precipitates were collected by filtration, washed with etherand dried to obtain 3.5 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.60 (s, 6H), 3.82 (bs, 2H), 4.63 to 4.97 (m, 4H),5.33 (d, J=5Hz, 1H), 5.83 to 6.22 (m, 1H), 6.86 to 8.17 (m, 5H).

Example 32

Synthesis of sodium7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl-3-cephem-4-carboxylate

In 40 ml of DMF were dissolved 1.6 g of2-(2-formylamino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid, 6.5 g ofdiphenylmethyl7-amino-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateand 1.29 g of 1-hydroxybenzotriazole and the solution was ice-cooled. Tothe solution was added 1.73 g of DCC and the mixture was stirred for 15minutes under ice-cooling and further stirred for one hour at roomtemperature. After filtration of the reaction mixture, 20 ml ofchloroform was added to the filtrate and the mixture was added dropwiseinto 2 liters of ether, and precipitates were collected by filtration,washed with ether and dried to obtain powder.

To 60 ml of ice-cooled methanol was added dropwise 1.1 ml of phosphorusoxychloride, and the powder obtained above was added to the mixture andthe mixture was stirred for 1.5 hours under ice-cooling. This reactionmixture was added dropwise into 1 liter of ether and precipitates werecollected by filtration, washed with ether and then powder obtained bydryness was purified through silica gel column to obtain powder.

This powder was added to a mixed solution of 10 ml of methylenechloride, 20 ml of trifluoroacetic acid and 5 ml of anisole, and themixture was stirred for 30 minutes under ice-cooling. This mixture wasadded dropwise into 500 ml of ether and precipitates were collected byfiltration, washed with ether and dried to obtain powder. This powderwas suspended in 50 ml of water, and dissolved by adding a 5% sodiumhydrogen cabonate solution at pH 6. Then, this solution was adsorbed toa column of which 150 ml of HP 20 was filled with water, washed withwater and then eluted with a methanol-water mixed solution. Aftercondensing fractions containing the title compound, freeze-dried toobtain 2.16 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 3.78 (s, 2H), 3.98 (s, 3H), 4.64 (bs, 2H), 4.81(s, 2H), 5.30 (d, J=5Hz, 1H), 5.75 to 6.08 (m, 1H), 6.98 (s, 1H), 7.95(s, 1H).

Example 33

Synthesis of diphenylmethyl7-[2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoyl-1-methylethoxyimino)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.hydrochloride

In 50 ml of DMF were dissolved 3.43 g of2-(2-formylamino-1,3-thiazol-4-yl)-2-[1-(3-formylcarbazoyl)-1-methylethoxyimino]aceticacid, 6.90 g of diphenylmethyl7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-3-cephem-4-carboxylate and 1.84 g of 1-hydroxybenzotriazole and thesolution was ice-cooled. To the solution was added 2.48 g of DCC, andthe mixture was stirred under ice-cooling for 10 minutes and furtherstirred at room temperature for one hour. After filtration of thereaction mixture, 20 ml of chloroform was added to the filtrate and themixture was added dropwise into 2 liters of ether. Precipitates werecollected by filtration, washed with ether and dried to obtain powder.This powder was purified through a column filled with 100 g of silicagel (eluent: a mixed solution of methanol-chloroform) and obtainedfractions containing the title compound was condensed, treated withether and powdered. To 80 ml of ice-cooled methanol was added 1.74 ml ofphosphorus oxychloride, and the powder previously obtained was added tothe mixture and the mixture was stirred under ice-cooling for one hour.This reaction mixture was added dropwise into 2 liters of ether, andprecipitates were collected by filtration, washed with ether and driedto obtain 6.05 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.62 (s, 6H), 2.61 (s, 3H), 3.92 (bs, 2H), 4.51(bs, 2H), 4.80 (s, 2H), 5.48 (d, J=5Hz, 1H), 5.97 to 6.28 (m, 1H), 7.10to 7.85 (m, 13H).

Example 34

Synthesis of sodium7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 30 ml of methylene chloride was suspended 2.76 g of diphenylmethyl7-[2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoyl-1-methylethoxyimino)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.dihydrochloride,and then 7.3 ml of N,O-bistrimethylsilylacetamide was added to thesuspension and the mixture was stirred for 15 minutes. After ice-coolingof this mixture, 0.92 g of 3,4-diacetoxybenzoic acid chloride was addedthereto and the mixture was stirred for 40 minutes. Thereafter, themixture was added dropwise into one liter of ether and precipitates werecollected by filtration and dried to obtain powder. After ice-cooling ofa mixed solution of 25 ml of trifluoroacetic acid, 7 ml of anisole and10 ml of methylene chloride, the powder previously obtained was addedthereto and the mixture was stirred for 30 minutes. The mixture wasadded dropwise into 500 ml of ether and precipitates were collected byfiltration and dried to obtain powder. The powder obtained was dissolvedin 50 ml of methanol and 1 ml of a 25% aqueous ammonia solution wasadded thereto, and the mixture was stirred at room temperature for onehour. The reaction mixture was condensed and the residue obtained wasdissolved in 50 ml of water. A pH of the solution was adjusted to 2 witha 2N hydrochloric acid and precipitated crystals were collected byfiltration. These crystals were suspended in 50 ml of water anddissolved at pH 7 with addition of a 5% sodium hydrogen carbonatesolution, and then adsorbed to a column filled with 100 ml of HP-20 andeluted with a mixed solution of methanol-water after washing with water.After collection of fractions containing the title compound andcondensation, the residue was freeze-dried to obtain 0.9 g of the titlecompound.

¹ H NMR (d₆ -DMSO) δ: 1.59 (s, 6H), 2.60 (s, 3H), 3.80 (bs, 2H), 4.51(bs, 2H), 4.70 (s, 2H), 5.33 (d, J=5Hz, 1H), 5.81 to 6.22 (m, 1H), 6.85to 7.55 (m, 5H).

Example 35

Synthesis of5-hydroxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine

(1) Synthesis of7-hydroxy-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine

In a mixture of 114.5 ml of glacial acetic acid and 50 ml of water wereadded 136 g of aminoguanidine bicarbonate and 1 ml of conc. nitric acidand the mixture was refluxed for 24 hours. An oily produce obtained byremoving water was dissolved in 800 ml of methanol, and 150 ml ofdimethyl acetylenedicarboxylate was added dropwise thereto and themixture was stirred at room temperature overnight. Precipitates werecollected by filtration, washed with water and dried to obtain 58 g ofthe title compound.

¹ H NMR (d₆ -DMSO) δ: 2.18 (s, 3H), 3.76 (s, 3H), 6.61 (s, 1H).

(2) Synthesis of7-hydroxy-5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidine

In 4 liters of ethanol was suspended 45.4 g of7-hydroxy-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and37.83 g of sodium borohydride was added little by little thereto, andthe mixture was then stirred at room temperature for 3 hours. A residueobtained by removing ethanol was dissolved in 2 liters of water, and 500ml of Amberlite IRC-50 (H⁺) (trade name) was added thereto and stirred.Subsequently, the mixture was filtered and after removing water from thefiltrate, 500 ml of methanol was added to the filtrate and the mixturewas stirred. Then, methanol was removed from the mixture to obtain aresidue. These procedures were repeated three times. Then, 500 ml ofethanol was added to the residue and the mixture was condensed.Precipitated crystals were collected by filtration, washed with ethanoland dried to obtain 39.35 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 2.26 (s, 3H), 4.32 (s, 2H), 5.78 (s, 1H).

(3) Synthesis of5-acetoxymethyl-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine

A mixture of 33.06 g of7-hydroxy-5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidine, 500 mlof DMF, 86 ml of anhydrous acetic acid and 1.5 g of p-toluenesulfonicacid was stirred in a bath at 50° C. for 6 hours. To an oily residueobtained by removing DMF was added 300 ml of isopropanol to dissolvetherein, and the solution was added dropwise in 4 liters of ether.Precipitates were collected by filtration and dried to obtain 38.08 g ofthe title compound.

¹ H NMR (d₆ -DMSO) δ: 2.26 (s, 3H), 2.50 (s, 3H), 5.16 (s, 2H), 6.14 (s,1H).

(4) Synthesis of5-acetoxymethyl-7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine

In 300 ml of phosphorus oxychloride was added dropwise 40 ml ofN,N-dimethylaniline, and 35 g of5-acetoxymethyl-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine was addedto the mixture and the mixture was stirred at 50° C. for one hour. Anoily residue obtained by removing phosphorus oxychloride was dissolvedin 500 ml of chloroform and ice-cooled. After addition of crushed iceand water to the mixture and stirring thereof, a chloroform layer wasseparated, washed with water and dried over anhydrous magnesium sulfate.Then, removing a solvent, an oily product was obtained. This was appliedto a silica gel column chromatography (eluent: chloroform) and fractionscontaining the title compound were condensed to obtain an oily product.This was allowed to stand to cool and crystallized to obtain 31 g of thetitle compound.

¹ H NMR (d6-CDC13) 67 : 2.23 (s, 3H), 2.66 (s, 3H), 5.35 (s, 2H), 7.36(s, 1H).

(5) Synthesis of5-hydroxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine

In 600 ml of ethanol was dissolved 31 g of5-acetoxymethyl-7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine, and 29.5g of thiourea was added thereto and the mixture was refluxed for 10minutes. The reaction mixture was ice-cooled and resulting precipitatedcrystal was collected by filtration. The crystal was dissolved in 600 mlof a 5% potassium hydroxide and the mixture was stirred for 30 minutes,ice-cooled and adjusted to pH 2 with 2N hydrochloric acid. Precipitatedcrystal was collected by filtration, washed with water and dried toobtain 16.33 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 2.58 (s, 3H), 4.57 (s, 2H), 7.21 (s, 1H).

Example 36

Synthesis of7-amino-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

In 120 ml of acetonitrile were suspended 9.8 g of5-hydroxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine and 13.6g of 7-aminocephalosporanic acid, and 22 ml of boron trifluoride-ethylether complex was added to the suspension and the mixture was stirred at50° C. for 3 hours. After cooling the reaction mixture, 250 ml of waterwas added thereto and the mixture was adjusted to pH 2 with conc.aqueous ammonia precipitated crystal was collected by filtration, washedwith water, washed with acetone and then dried to obtain 11.6 g of thetitle compound.

¹ H NMR (CF3COOD) δ: 2.86 (s, 3H), 3.88 (s, 2H), 5.04 (broad s, 2H),5.34 (s, 2H), 5.60 (s, 2H), 8.24 (s, 1H).

Example 37

Synthesis of diphenylmethyl7-amino-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In a suspension of 11.6 g of7-amino-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid, 70 ml of methanol and 200 ml of methylene chloride was addeddropwise, while stirring, diphenyldiazomethane synthesized from 15.7 gof benzophenonehydrazone, 17.3 g of mercuric oxide (yellow) and 130 mlof n-hexane, in 50 ml of methylene chloride solution, and the mixturewas stirred at room temperature overnight. After the reaction mixturewas condensed, ether was added thereto to crystalize, and crystal wascollected by filtration and dried to obtain 15.9 g of the titlecompound.

¹ H NMR (d₆ -DMSO+CDCl₃) δ: 2.57 (s, 3H), 3.74 (broad s, 2H), 4.36(broad s, 2H), 4.77 (s, 2H), 4.93 to 5.22 (m, 2H), 7.04 to

7.78 (m, 12H).

Example 38

Synthesis of sodium7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 30 ml of DMF were dissolved 3.22 g of2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}aceticacid.hydrochloride, 5.17 g of diphenylmethyl7-amino-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateobtained in Example 37 and 1.38 g of 1-hydroxybenzotriazole andice-cooled. Then, 1.86 g of DCC was added thereto and the mixture wasstirred for 15 minutes under ice-cooling, and further stirred at roomtemperature for 30 minutes. After the reaction mixture was filtered, 15ml of chloroform was added thereto and the mixture was added dropwiseinto 4 liters of ether. precipitates were collected by filtration,washed with ether and then dried. Powder obtained was purified throughsilica gel column chromatography to obtain powder. A mixed solution of30 ml of trifluoroacetic acid and 8 ml of anisole was ice-cooled and thepowder previously obtained was added thereto, and the mixture wasstirred for 30 minutes and added dropwise into 400 ml of ether,precipitates were collected by filtration, washed with ether and thendried to obtain powder. The powder was suspended in 200 ml of water anddissolved at pH 7 by adding a 5% sodium hydrogencarbonate solution.After the resulting solution was adsorbed to 200 ml of HP 20 columnfilled with water, it was washed with water Subsequently, the mixturewas eluted with a 50% methanol-water After evaporation of methanol, theresidue was freeze-dried to obtain 3.75 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.60 (s, 6H), 2.55 (s, 3H), 3.82 (broad s, 2H),4.54 (broad s, 2H), 4.73 (s, 2H), 5.38 (d, J=5 Hz, 1H), 5.92 to 6.26 (m,1H), 6.80 to 7.23 (m, 5H).

Example 39

Synthesis of sodium7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino)acetamido]-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 30 ml of DMF were dissolved 1.6 g of2-(2-formylamino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid, 5.17 g ofdiphenylmethyl7-amino-3-[(5-hydroxymethyl-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateand 1.38 g of 1-hydroxybenzotriazole and ice-cooled. Then, 1.86 g of DCCwas added thereto and the mixture was stirred for 15 minutes underice-cooling, and further stirred at room temperature for one hour. Afterthe reaction mixture was filtered, 15 ml of chloroform was added to thefiltrate and the mixture was added dropwise into 2 liters of ether.Precipitates were collected by filtration, washed with ether and thendried. To an ice-cooled 60 ml of methanol was added dropwise 1.45 ml ofphosphorus oxychloride, and to the mixture was added the powderpreviously obtained, and the mixture was stirred for one hour underice-cooling. The reaction mixture was added dropwise into 800 ml ofether and precipitates were collected by filtration, washed with etherand then dried to obtain powder. The powder was purified through silicagel column chromatography to obtain a powder. The powder was added to amixed solution of 30 ml of trifluoroacetic acid and 8 ml of anisole andthe mixture was stirred for 30 minutes under ice-cooling. The resultingmixture was added dropwise into 400 ml of ether, and precipitates werecollected by filtration, washed with ether and dried to obtain a powder.After this powder was suspended in 50 ml of water and dissolved at pH 6by addition of a 5% sodium hydrogencarbonate solution, it was adsorbedto 100 ml of HP 20 column filled with water and then washed with water.Subsequently, the mixture was eluted with a methanol-water mixedsolution. After condensation of fractions containing the title compound,the residue was freeze-dried to obtain 3.0 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 2.62 (s, 3H), 3.88 (broad s, 2H), 4.10 (s, 3H),4.68 (broad s, 2H), 4.79 (s, 2H), 5.40 (d, J=5 Hz, 1H), 5.79 to 6.14 (m,1H), 7.18 (s, 1H), 7.77 (s, 1H).

Example 40

Synthesis of2,5-bis(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine

(1) Synthesis of7-hydroxy-2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidine

In 4 liters of ethanol was suspended 48.94 g of7-hydroxy-2-hydroxymethyl-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine,and 33 g of sodium borohydride was added little by little thereto andthen the mixture was stirred at room temperature for 3 hours and thenrefluxed for 4 hours. A residue obtained by removing ethanol wasdissolved in 2 liters of water, and 500 ml of Amberlite IRC-50 (H⁺)(trade name) was added thereto and stirred. Subsequently, the mixturewas filtered and after removing water from the filtrate, 500 ml ofmethanol was added to the filtrate and the mixture was stirred. Then,methanol was removed from the mixture to obtain a residue. Theseprocedures were repeated three times. Then, 500 ml of ethanol was addedto the residue and the mixture was condensed. Precipitated crystal wascollected by filtration, washed with ethanol and dried to obtain 39.35 gof the title compound.

¹ H NMR (d₆ -DMSO) δ: 4.53 (s, 2H), 4.62 (s, 2H), 6.11 (s, 1H).

(2) Synthesis of2,5-bis(acetoxymethyl)-7-hydroxy-2-methyl-s-triazolo[1,5-a]pyrimidine

A mixture of 34.96 g of7-hydroxy-2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidine, 850 ml ofDMF, 120 ml of anhydrous acetic acid and 3.42 g of p-toluenesulfonicacid was stirred in a bath at 50° C. for 2 hours. To an oily residueobtained by removing DMF was added 250 ml of ethanol to dissolvetherein, and the solution was added dropwise in 4 liters of ether.Precipitates were collected by filtration and dried to obtain 30.57 g ofthe title compound.

¹ H NMR (d₆ -DMSO) δ: 2.11 (s, 3H), 2.17 (s, 3H), 4.98 (s, 2H), 5.17 (s,2H), 5.80 (s, 1H).

(3) Synthesis of7-chloro-2,5-bis(acetoxymethyl)-s-triazolo[1,5-a]pyrimidine

In 300 ml of phosphorus oxychloride was added dropwise 28 ml ofN,N-dimethylaniline, and 30.5 g of2,5-bis(acetoxymethyl)-7-hydroxy-s-triazolo[1,5-a]pyrimidine was addedto the mixture and the mixture was stirred at 50° C. for 1.5 hours. Anoily residue obtained by removing phosphorus oxychloride was dissolvedin 500 ml of chloroform and ice-cooled. After addition of crushed iceand water to the mixture and stirring thereof, a chloroform layer wasseparated, washed with water and dried over anhydrous magnesium sulfate.Then, the mixture was condensed. This was applied to a silica gel columnchromatography (eluent: chloroform) and fractions containing the titlecompound were condensed to obtain 14 g of the title compound as an oilyproduct.

¹ H NMR (d₆ -CDCl₃) δ: 2.35 (s, 3H), 2.31 (s, 3H), 5.44 (s, 2H), 5.52(s, 2H), 7.44 (s, 1H).

(4) Synthesis of2,5-bis(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine

In 300 ml of ethanol was dissolved 14 g of7-chloro-2,5-bis(acetoxymethyl)-s-triazolo[1,5-a]pyrimidine, and 10.7 gof thiourea was added thereto and the mixture was refluxed for 10minutes. After removing ethanol from the reaction mixture, the residuewas dissolved in 230 ml of a 5% potassium hydroxide. The mixture wasstirred for 30 minutes, ice-cooled and adjusted to pH 2 with 2Nhydrochloric acid. precipitated crystal was collected by filtration,washed with water and dried to obtain 7.16 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 4.58 (s, 2H), 4.77 (s, 2H), 7.19 (s, 1H).

Example 41

Synthesis of7-amino-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid

In 80 ml of acetonitrile were suspended 7.1 g of2,5-bis(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine and 9.1 gof 7-aminocephalosporanic acid, and 15 ml of boron trifluoride-ethylether complex was added to the suspension and the mixture was stirred at50° C. for 3 hours. After cooling the reaction mixture, 200 ml of waterwas added thereto and the mixture was adjusted to pH 2 with conc.aqueous ammonia. Precipitated crystal was collected by filtration,washed with water, washed with acetone and then dried to obtain 5.34 gof the title compound.

¹ H NMR (CF₃ COOD) δ: 3.97 (s, 2H), 4.98 (broad s, 2H), 5.29 (s, 2H),5.46 (s, 2H), 5.54 (s, 2H), 8.26 (s, 1H).

Example 42

Synthesis of diphenylmethyl7-amino-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In a suspension of 5.3 g of7-amino-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylicacid, 35 ml of methanol and 100 ml of methylene chloride was addeddropwise, while stirring, diphenyldiazomethane synthesized from 6.9 g ofbenzophenonehydrazone, 7.6 g of mercuric oxide (yellow) and 70 ml ofn-hexane, in 30 ml of methylene chloride solution, and the mixture wasstirred at room temperature overnight. After the reaction mixture wascondensed, ether was added thereto to crystalize, and crystal wascollected by filtration and dried to obtain 7.28 g of the titlecompound.

¹ H NMR (d₆ -DMSO+CDCl₃) δ: 3.75 (broad s, 2H), 4.34 (broad s, 2H), 4.77to 5.34 (m, 6H), 6.96 to 7.75 (m, 12H).

Example 43

Synthesis of sodium7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 30 ml of DMF were dissolved 3.22 g of2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}aceticacid.hydrochloride, 5.32 g of diphenylmethyl7-amino-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateobtained in Example 42 and 1.38 g of 1-hydroxybenzotriazole andice-cooled. Then, 1.86 g of DCC was added thereto and the mixture wasstirred for 15 minutes under ice-cooling, and further stirred at roomtemperature for one hour. After the reaction mixture was filtered, 15 mlof chloroform was added thereto and the mixture was added dropwise into2 liters of ether, precipitates were collected by filtration, washedwith ether and then dried. Powder obtained was purified through silicagel column chromatography to obtain powder. A mixed solution of 30 ml oftrifluoroacetic acid and 8 ml of anisole was ice-cooled and the powderpreviously obtained was added thereto, and the mixture was stirred for30 minutes and added dropwise into 400 ml of ether. Precipitates werecollected by filtration, washed with ether and then dried to obtainpowder. The powder was suspended in 200 ml of water and dissolved at pH7 by adding a 5% sodium hydrogencarbonate solution. After the resultingsolution was adsorbed to 200 ml of HP 20 column filled with water, itwas washed with water. Subsequently, the mixture was eluted with a 50%methanol-water. After evaporation of methanol, the residue wasfreeze-dried to obtain 4.16 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.60 (s, 6H), 3.86 (broad s, 2H), 4.60 (broad s,2H), 4.78 (s, 4H), 5.40 (d, J=5 Hz, 1H), 5.87 to 6.27 (m, 1H), 6.94 to7.72 (m, 5H).

Example 44

Synthesis of7-[2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoyl-1-methylethoxyimino)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.dihydrochloride

In 35 ml of DMF were dissolved 2.5 g of2-(2-formylamino-1,3-thiazol-4-yl)-2-[1-(3-formylcarbazoyl)-1-methylethoxyimino]aceticacid, 5 g of diphenylmethyl7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateand 1.33 g of 1-hydroxybenzotriazole and the solution was ice-cooled. Tothe solution was added 1.8 g of DCC, and the mixture was stirred underice-cooling for 10 minutes and further stirred at room temperature forone hour. After filtration of the reaction mixture, 10 ml of chloroformwas added to the filtrate and the mixture was added dropwise into oneliter of ether. Precipitates were collected by filtration, washed withether and dried to obtain a powder. This powder was purified through acolumn filled with 50 g of silica gel to obtain a powder. A mixedsolution of 30 ml of trifluoroacetic acid, 8 ml of anisole and 15 ml ofmethylene chloride was ice-cooled, and the powder previously obtainedwas added to the mixed solution and the mixture was stirred for 30minutes. This reaction mixture was added dropwise into 400 ml of ether,precipitates were collected by filtration and dried to obtain 4.15 g ofthe title compound.

¹ H NMR (d₆ -DMSO) δ: 1.61 (s, 6H), 2.68 (s, 3H), 3.83 (s, 2H), 4.60(broad s, 2H), 4.78 (s, 2H), 5.37 (d, J=5 Hz, 1H), 5.80 to 6.18 (m, 1H),7.27 (s, 1H), 7.60 (s, 1H).

Example 45

Synthesis of sodium7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzylidene)carbazoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 40 ml of methanol was dissolved 3.8 g of7-[2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoyl-1-methylethoxyimino)acetamido]-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.dihydrochloride,and then 1.03 g of protocatechuic aldehyde was added to the solution andthe mixture was stirred at room temperature for 1.5 hours. The mixturewas poured into 400 ml of ether and precipitates were collected byfiltration, washed with ether and dried to obtain a powder. The powderwas suspended in 100 ml of water and dissolved at pH 6 by addition of a5% sodium hydrogencarbonate solution. After the resulting solution wasadsorbed to 100 ml of HP 20 column filled with water, it was washed withwater. Subsequently, the mixture was eluted with methanol-water. Afterconensation of fractions containing the title compound, the residue wasfreeze-dried to obtain 3.15 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.63 (s, 6H), 2.68 (s, 3H), 3.82 (broad s, 2H),4.62 (broad s, 2H), 4.62 (broad s, 2H), 4.82 (s, 2H), 5.40 (d, J=5 Hz,1H), 5.92 to 6.22 (m, 1H), 6.98 to 7.76 (m, 5H), 8.58 (s, 1H).

Example 46

Synthesis of pivaloyloxymethyl7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 80 ml of acetone was suspended 16.9 g of7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-3-cephem-4-carboxylicacid and ice-cooled, and then 5.98 ml of1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) was added dropwise to thesolution and the mixture was stirred for 30 minutes. After 9.68 g ofpivaloyloxymethyl iodide was added dropwise to the mixture, the mixturewas stirred at room temperature for 20 minutes. After the reactionmixture was poured into a mixed solution of 280 ml of ethyl acetate and200 ml of water and stirred, an organic layer was separated therefrom,washed with water, further washed with a saturated saline solution anddried over anhydrous magnesium sulfate. By removing a solvent, an oilyproduct was obtained. This oily product was purified through silica gelcolumn chromatography. To the oily product obtained was added ether topowderize, and it was collected by filtration and dried to obtain 10.17g of the title compound.

¹ H NMR (d₆ -CDCl₃) δ: 1.22 (s, 9H), 2.68 (s, 3H), 3.57 (s, 3H), 3.72(s, 2H), 4.43 (s, 2H), 4.77 (s, 2H), 4.96 (ABq, 2H), 5.96 (broad s, 2H),7.02 (s, 1H).

Example 47

Synthesis of pivaloyloxymethyl7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate

In 50 ml of DMF were added 3.43 g of2-(2-formylamino1,3-thiazol-4-yl)-2-methoxyiminoacetic acid, 10.1 g ofpivaloyloxymethyl7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateand 2.76 g of 1-hydroxybenzotriazole and ice-cooled, and 3.71 g of DCCwas added to the solution and the mixture was stirred for 1.5 hoursunder ice-cooling. After filtration of the reaction mixture, 20 ml ofchloroform was added to the filtrate, and the mixture was added dropwiseinto 4 liters of ether. Precipitates were collected by filtration anddried to obtain a powder. To 1.57 ml of phosphorus oxychloride was added80 ml of ice-cooled methanol, and the powder previously obtained wasadded thereto and the mixture was stirred for 1.5 hours underice-cooling. After the mixture was condensed to a half, the residue wasadded dropwise to a mixed solution of 200 ml of water and 200 ml ofethyl acetate and the mixture was neutralized with addition of sodiumhydrogencarbonate. An organic layer was separated, washed with water andthen dried over anhydrous magnesium sulfate, followed by evaporation ofa solvent to obtain an oily product. The oily product was purifiedthrough silica gel column chromatography. To the oily product obtainedwas added ether to powderize, and it was collected by filtration anddried to obtain 3.4 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.20 (s, 9H), 2.62 (s, 3H), 3.42 (s, 3H), 3.79(bs, 2H), 4.02 (s, 3H), 4.48 (bs, 2H), 4.65 (s, 2H), 5.28 (d, J=5 Hz,1H), 5.73 to 6.16 (m, 3H), 6.96 (s, 1H), 7.42 (s, 1H).

Example 48

Synthesis of 7-[2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoyl-1-methylethoxyimino)acetamido]-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.dihydrochloride

In 35 ml of DMF were dissolved 2.5 g of2-(2-formylamino1,3-thiazol-4-yl)-2-[1-(3-formylcarbazoyl)-1-methylethoxyimino]aceticacid, 5.12 g of diphenylmethyl7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateand 1.33 g of 1-hydroxybenzotriazole and the solution was ice-cooled. Tothe solution was added 1.8 g of DCC, and the mixture was stirred underice-cooling for 10 minutes and further stirred at room temperature forone hour. After filtration of the reaction mixture, 10 ml of chloroformwas added to the filtrate and the mixture was added dropwise into oneliter of ether, precipitates were collected by filtration, washed withether and dried to obtain a powder. This powder was purified through acolumn filled with 50 g of silica gel to obtain a powder. A mixedsolution of 30 ml of trifluoroacetic acid, 8 ml of anisole and 15 ml ofmethylene chloride was ice-cooled, and the powder previously obtainedwas added to the mixed solution and the mixture was stirred for 30minutes. This reaction mixture was added dropwise into 400 ml of ether,precipitates were collected by filtration and dried to obtain a powder.To 1.45 ml of phosphorus oxychloride was added 40 ml of ice-cooledmethanol, and the powder previously obtained was added thereto and themixture was stirred for one hour under ice-cooling. The mixture wasadded dropwise into 400 ml of ether, precipitates were collected byfiltration and dried to obtain 4.0 g of the title compound.

¹ H NMR (d₆ -DMSO) δ: 1.63 (s, 6H), 2.69 (s, 3H), 3.48 (s, 3H), 3.88 (s,2H), 4.61 (broad s, 2H), 4.76 (s, 2H), 5.42 (d, J=5 Hz, 1H), 5.87 to6.21 (m, 1H), 7.30 (s, 1H), 7.58 (s, 1H).

Test example 1

20 mg/kg of compound obtained in the above Example 19 was administeredparenterally to cynomolgus monkeys and the half-life in blood wasmeasured. The results are shown in Table 1.

The concentration of the compound was measured according to HPLC method.Novapack C18 or Microbondapack C18 (both trade name, produced by WatersCo.) was used for analysis. Further, cefpiramide was used as a controldrug.

                  TABLE 1                                                         ______________________________________                                                   Half-life in blood                                                 Compound   of cynomolgus monkeys (hours)                                      ______________________________________                                        Example 19 2.6                                                                Cefpiramide                                                                              2.5                                                                ______________________________________                                    

As is apparent from Table 1, the half-life in blood of the compoundaccording to the present invention is the same as that of cefpiramide inthe case of cynomolgus monkeys. Among the existing cephalosporins,cefpiramide is known as a cephalosporin having a long half-life inblood. On the other hand, the experimental results that the half-life inblood of β-lactam compounds in monkey and human being are mutuallywell-related has been reported by U. Sawada et al. (J. Pharmaco.,Biopharma., 12, 241 (1984)). Accordingly, the results in Table 1 suggestthat the half-life in blood of said compound would be the same as thatof cefpiramide for human beings. High usefulness such that the same orhigher clinical efficacy could be obtained with a smaller number ofadministration, when compared with other many cephalosporins havingshorter half-life, can be expected.

Test example 2

The minimum inhibitory concentration (MIC) of the compounds obtained inthe above Examples were measured according to the standard method ofJapan Society of Chemotherapy. The results are shown in Tables 2A and 2Band Table 3.

In Tables 2A and 2B and Table 3, ceftazidime (CAZ) was used as a controlcompound.

As is apparent from Tables 2A and 2B, the compound of the presentinvention is effective to gram positive bacteria and gram negativebacteria and has wide range of antibacterial spectrum. Particularly, thecompound of the present invention exhibits stronger antibacterialactivities against glucose non-fermenting bacteria including Pseudomonasaeruginosa than the third generation cephalosporin.

As is apparent from Table 3, the compound of the present inventionexhibits strong antibacterial activities against clinical isolatesresistant to ceftazidime, one of the third generation cephalosporins.

                                      TABLE 2A                                    __________________________________________________________________________                    MIC (μg/ml)                                                                Example                                                                            Example                                                                            Example                                                                            Example                                                                            Example                                                                            Example                              Strain          19   25   31   38   43   45   CAZ                             __________________________________________________________________________    Staphylococcus aureus Smith                                                                   1.56 3.13 12.5 3.13 3.13 3.13 6.25                            Staphylococcus aureus IAA498                                                                  6.25 6.25 25   6.25 6.25 6.25 12.5                            Escherichia coli ML4704                                                                       0.012                                                                              0.025                                                                              0.025                                                                              0.1  0.1  0.39 0.05                            Escherichia coli GN5482                                                                       0.025                                                                              0.025                                                                              0.05 0.05 0.1  0.1  1.56                            Klebsiella pneumoniae 4at521                                                                  0.012                                                                              0.025                                                                              0.025                                                                              0.012                                                                              0.2  0.39 0.1                             Enterobacter cloacae GN7471                                                                   6.25 3.13 0.78 1.56 1.56 1.56 3.13                            Enterobacter cloacae 908RN                                                                    6.25 6.25 1.56 1.56 3.13 12.5 100                             Citrobacter freundii GN7391                                                                   12.5 12.5 1.56 6.25 6.25 12.5 >100                            Serratia marcescens GN10857                                                                   0.78 0.39 0.78 0.39 0.39 0.78 3.13                            Proteus vulgris GN7919                                                                        1.56 1.56 3.13 1.56 3.13 12.5 1.56                            Pseudomonas aeruginosa GN10362                                                                0.05 0.05 0.025                                                                              0.1  0.1  0.78 1.56                            Pseudomonas aeruginosa 4au542                                                                 0.2  0.2  0.2  0.2  0.2  0.78 3.13                            Pseudomonas aeruginosa 5D58-1                                                                 0.05 0.05 0.1  0.1  0.1  0.39 1.56                            Pseudomonas cepacia OF189                                                                     0.025                                                                              --   --   0.025                                                                              0.025                                                                              0.2  6.25                            Pseudomonas maltophilia OF247                                                                 0.39 --   --   0.39 0.78 12.5 3.13                            __________________________________________________________________________

                                      TABLE 2B                                    __________________________________________________________________________                    MIC (μg/ml)                                                                Example                                                                             Example                                                                            Example                                                                             Example                                                                             Example                                                                             Example                                                                             Example                    Strain          21    18   27    32    44    48    39    CAZ                  __________________________________________________________________________    Staphylococcus aureus Smith                                                                   3.13  0.39 0.78  6.25  6.25  6.25  0.78  6.25                 Staphylococcus aureus IAA498                                                                  6.25  12.5 25    12.5  12.5  12.5  12.5  12.5                 Escherichia coli ML4704                                                                       0.39  0.025                                                                              0.05  0.1   0.2   0.2   0.05  0.05                 Escherichia coli GN5482                                                                       0.78  0.1  0.39  0.2   0.39  0.78  0.1   1.56                 Klebsiella pneumoniae 4at521                                                                  0.78  0.39 1.56  0.2   3.13  6.25  0.78  0.1                  Enterobacter cloacae GN7471                                                                   6.25  3.13 6.25  6.25  25    50    3.13  3.13                 Enterobacter cloacae 908RN                                                                    100   50   50    100   >100  >100  50    100                  Citrobacter freundii GN7391                                                                   >100  50   50    100   100   >100  25    >100                 Serratia marcescens GN10857                                                                   12.5  12.5 25    25    50    100   25    3.13                 Proteus vulgris GN7919                                                                        3.13  25   25    50    50    50    6.25  1.56                 Pseudomonas aeruginosa GN10362                                                                12.5  100  100   100   25    50    100   1.56                 Pseudomonas aeruginosa 4au542                                                                 12.5  100  >100  >100  100   >100  >100  3.13                 Pseudomonas aeruginosa 5D58-1                                                                 6.25  100  100   >100  25    50    100   1.56                 Pseudomonas cepacia OF189                                                                     --    --   --    --    50    100   25    6.25                 Pseudomonas maltophilia OF247                                                                 --    --   --    --    50    100   50    3.13                 __________________________________________________________________________

                  TABLE 3                                                         ______________________________________                                                         MIC (μg/ml)                                               Strain             Example 19                                                                              CAZ                                              ______________________________________                                        Enterobacter cloacae 5D52-2                                                                      0.39      12.5                                             Enterobacter cloacae 5D83-2                                                                      0.78      12.5                                             Enterobacter cloacae IV25                                                                        1.56      50                                               Enterobacter cloacae IY247                                                                       6.25      12.5                                             Enterobacter cloacae 908RN                                                                       12.5      >100                                             Citrobacter freundii 5D60-1                                                                      1.56      >100                                             Citrobacter freundii 1R523                                                                       0.78      25                                               Citrobacter freundii 1R524                                                                       0.39      25                                               Citrobacter freundii 1R526                                                                       0.39      25                                               Citrobacter freundii 1R527                                                                       0.2       25                                               Citrobacter freundii 1U589                                                                       1.56      100                                              Citrobacter freundii 1U592                                                                       25        100                                              Citrobacter freundii GM7391                                                                      6.25      >100                                             ______________________________________                                    

Example 49

The following pharmaceutical for injection was prepared.

Sodium7-{2-[2-amino-1,3-thiazol-4-yl]-2-[1-(3-(3,4-dihydroxybenzoyl)carbamoyl)-1-methylethoxyimino]acetamido}-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylateobtained in Example 19 . . . 500 mg

Sterile distilled water . . . amount so as to give a total of about 5ml.

The above compound was dissolved in the sterile distilled water toobtain the pharmaceutical for injection.

We claim:
 1. A compound represented by the formula (VII'): ##STR23##where at least one of R₂, R₃ and R₉ represent a group represented by theformula: --A--OR₄ where R₄ represents a hydrogen or a lower alkyl group;and A represents a straight or branched alkylene group having 1 to 6carbon atoms; and a remaining group or groups are each independently ahydrogen atom; a cyano group; a lower alkyl group which may besubstituted by a halogen atom; a carbamoyl group which may besubstituted by a lower alkyl group; a cycloalkyl group; or a carboxylgroup which may be substituted by a protective group or an eliminatablegroup which is easily hydrolyzable in a human body, and also when R₉ is--A--OR₄, R₂ and R₃ may be combined with each other to form an alkylenegroup having 3 to 4 carbon atoms; Z represents a nitrogen atom or agroup represented by the formula: C--R₁₀ where R₁₀ represents a hydrogenatom, a carboxyl group or a lower alkyl group which may be substitutedby a hydroxy group or a lower alkoxy group; and X represents a hydrogenatom, a lower alkyl group, a lower alkoxy group or a halogen atom.
 2. Acompound according to claim 1, wherein the protective group is selectedfrom the group consisting of a diphenylmethyl group, a t-butyl group, ap-nitrobenzyl group and a trimethylsilyl group and the eliminatablegroup which is easily hydrolyzable in a human body is selected from thegroup consisting of an acetoxymethyl group, an α-acetoxyethyl group, apivaroyloxymethyl group, an ethoxycarbonyloxymethyl group, anα-methoxycarbonyloxymethyl group, an α-methoxycarbonyloxyethyl group, anα- ethoxycarbonyloxyethyl group, a 1-indanyl, a phthalidyl group, and a5-methyl-2-oxo-1,3-dioxol-4-yl-methyl group.
 3. A compound according toclaim 2, wherein the cycloalkyl group is selected from the groupconsisting of a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup and a cyclohexyl group.